DESCRIPTION: (Applicant's Abstract) The abuse of methamphetamine (METH) has escalated in recent years and effective treatments to curtail its use are not yet available. Our preliminary results demonstrate that a-lobeline (LOB), a weakly basic lipophilic alkaloid, binds to the high affinity nicotinic receptor binding site (a4P2 subtype) and acts as an antagonist at the nicotinic receptor subtype which evokes dopamine (DA) release (purportedly, the a3P2 subtype). LOB also inhibits the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2), but does not inhibit monoamine oxidase (MAO). Moreover, LOB inhibits amphetamine (AMPT)-evoked DA release and METH self-administration in rats. Our preliminary results suggest that VMAT2 may be an important new therapeutic target for the treatment of METH abuse. With this in mind, we have begun synthesizing a series of LOB analogs to target VMAT2. The long-term goal of this proposal is to develop our lead LOB analog, 2R,6S-N-methyl-2,6-<E-(cis-phenylethenyl)piperidine (meso-transdiene, MTD), and other structurally related MTD analogs as novel treatments for METH abuse. MTD is a synthetic derivative of LOB, which unlike LOB, has negligible affinity for nicotinic receptors, and moreover, targets DA transporters. Structural analogs of MTD will be evaluated in neurochemical and behavioral assays to develop the structure activity relationships (SARs) for the VMAT2 pharmacophore. Experiments are designed to test two specific hypotheses. First, pretreatment of rats with MTD or its structural analogs will reduce the cytosolic pool of DA available for METH-induced reverse transport of DAT via an interaction with VMAT2, and thereby decrease METH-induced DA release from the presynaptic terminal. Second, pretreatment of rats with MTD or its analogs will diminish METE self-administration. The interaction of the analogs with nicotinic receptors and with DATMll also be evaluated, since LOB acts at these sites as well. Results from the latter assays will direct the SAR towards greater selectivity for VMAT2. MTD analogs which potently inhibit METH-induced DA release in vitro and which do not interact at nicotinic receptors will be assessed for their ability to decrease METH self-administration in rats. We predict that MTD analogs with high potency and selectivity for VMAT2 will be the best candidates for the treatment of METH abuse. Thus, these studies will pioneer the development of a novel class of therapeutic agents which target VMAT2 and have potential as efficacious treatments for METH abuse.